We propose a case-only study of Head and Neck Squamous Cell Cancer (HNSCC) with the goal of defining the carcinogen-induced patterns of somatic inactivation of genes in the Retinoblastoma pathway. HNSCC occurs in over 42,000 men and women annually in the United States, resulting in over 13,000 deaths per year. Recent developments in the molecular pathology of this disease have delineated the important critical genes that are altered in the genesis of HNSCC. Further, as these genes have been identified and pathologists have begun to understand their relationship with disease, groups of genes have become identified as members of multiple components, critical pathways in cellular regulation. Indeed, it is now known that somatic cell inactivation can occur in multiple ways; gene mutation has long been realized as a critical type of alteration, but homozygous gene loss and epigenetic silencing have also recently been recognized as common and important mechanisms of somatic gene alteration in HNSCC. Most molecular pathology has considered only frequency of gene inactivation as important, rather than examining the type of alteration and the possible consequences of the precise nature of somatic alteration. We have developed a novel hypothesis based upon our observation of a strong, significant association of smoking with the precise nature of inactivation of the p161NK4A gene in the PRB pathway. Our new working model for the mechanism of action of carcinogens predicts the characteristics of susceptible individuals. In essence, we hypothesize that homozygous deletion events commonly occur in, and therefore define, susceptible individuals. Epigenetic inactivation of p161NK4A is more often found in patients with relatively longer smoking histories and these patients then are relatively "resistant" to the effects of tobacco carcinogens. We propose to confirm, extend and further develop this model of HNSCC susceptibility using the resources of the Pl.'s already funded, independent, case series that is derived from a population-based case control study currently in its fourth year of enrolling cases. [unreadable] [unreadable]